Studies on the mechanisms underlying renal tubular deficiency due to the lack of the expression and function of CLCN5, a gene responsible for Dent's disease

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Dent's disease is a X-linked recessive nephrolithiasis associated with various renal dysfunctions such as proteinuria and hypercalciuria. Recently, CLCN5, a gene encoding chloride channel ClC-5, was found to be responsible for Dent's disease, though the precise role of ClC-5 is not known at this moment. ClC-5 is highly expressed in the kidney, where the channel is involved in the acidification of endosomes, an important step for receptor-mediated endocytosis. On the other hand, proteins filtered through glomerulus are efficiently taken up by tubular cells by receptor-mediated endocytosis. In the present study, I examined the role of ClC-5 in renal handling of proteins and calcium.Cultured renal epithelial cells OK were used as a model system, which I confirmed the expression of ClC-5. When cells were treated with chloride channel inhibitors, the endocytosis of FITC-labeled albumin was inhibited. In addition, the uptake of calcium by OK cells was inhibited by chloride channel inhibitors as well as by anti-ClC-5 antibody. Therefore, C1C-5 would have an important role for the endocytosis of filtered protein and calcium uptake in the kidney. These results may explain the proteinuria and hypercalciuria observed in Dent's disease, in which ClC-5 is lacking.